Fragile X spectrum disorder (FXSD) includes: fragile X syndrome (FXS), fragile X-associated tremor
ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), as well as other medical,
psychiatric and neurobehavioral problems associated with the premutation and gray zone alleles. FXS is the most common monogenetic
cause of autism (ASD) and intellectual disability (ID). The understanding of the neurobiology of FXS has led to many targeted
treatment trials in FXS. The first wave of phase II clinical trials in FXS were designed to target the mGluR5 pathway; however the results
did not show significant efficacy and the trials were terminated. The advances in the understanding of the GABA system in FXS have
shifted the focus of treatment trials to GABA agonists, and a new wave of promising clinical trials is under way. Ganaxolone and allopregnanolone
(GABA agonists) have been studied in individuals with FXSD and are currently in phase II trials. Both allopregnanolone
and ganaxolone may be efficacious in treatment of FXS and FXTAS, respectively. Allopregnanolone, ganaxolone, riluzole, gaboxadol,
tiagabine, and vigabatrin are potential GABAergic treatments. The lessons learned from the initial trials have not only shifted the targeted
system, but also have refined the design of clinical trials. The results of these new trials will likely impact further clinical trials for FXS
and other genetic disorders associated with ASD.
Keywords: GABA, GABAA, GABA system, Fragile X Spectrum Disorder, FXSD, Fragile X Syndrome, FXS, Fragile X-associated Tremor
Ataxia Syndrome, FXTAS, Targeted treatments, Clinical trials, ASD treatments, Autism.
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